Formation of volatile nitrosamines by drug-nitrite interactions under physiological conditions

Twenty-eight drugs, most of which are tertiary amines, were tested for the formation of volatile nitrosamines by reaction with nitrite under physiological conditions; the drugs (10mM) were incubated with nitrite ( 40mM ) at pH 3.0, 37 degrees for 1 and 4 hr. The volatile nitrosamines formed were determined by gas chromatography-thermal energy analysis. Of the 28 drugs, 24 formed measurable amounts of volatile nitrosamines that are known carcinogens. The yields of nitrosodimethylamine (NDMA) from aminopyrine (55-65%) and minocycline (11%) were higher than that from dimethylamine under the same conditions. This result suggests that there may be a pathway not involving the secondary amine (dimethylamine) as an intermediate in the formation of NDMA from minocycline as well as from aminopyrine, Tolazamide gave rise to nitrosopiperidine ( NPIP ) in addition to nitrosohexamethyleneimine ( NHXI ), formation of which was expected from the chemical structure of tolazamide, and the yield of NPIP (2-7%) was higher than that of NHXI (0.2-1.2%). Ascorbic acid ( 40mM ) was effective in decreasing the formation of nitrosamines from drugs by reaction with nitrite, although the blocking effects varied between 88 and 100% depending on the drugs tested or on the nitrosamines formed.